What to do for a patient taking Eliquis (apixaban) with an elevated International Normalized Ratio (INR) greater than 8.0?

INR >8.0 in a Patient Taking Apixaban (Eliquis)

The elevated INR is a laboratory artifact caused by apixaban's interference with INR testing and does not reflect vitamin K-dependent coagulation factor deficiency—therefore, do not administer vitamin K or warfarin reversal agents. 1, 2

Critical Understanding: Apixaban Does Not Cause True INR Elevation

• Apixaban is a direct Factor Xa inhibitor, not a vitamin K antagonist (VKA), and INR testing is not validated for monitoring its anticoagulant effect. 1, 2

• Apixaban artificially prolongs prothrombin time (PT) and INR through direct Factor Xa inhibition in the laboratory assay, with median INR elevations typically ranging from 1.4-1.7 in most patients. 1, 2

• Extreme INR elevations (>8.0 or even >20) have been documented with apixaban, particularly in patients with end-stage renal disease on hemodialysis, but these represent assay interference rather than true coagulopathy. 1

• One case report documented an INR of 27.42 in a patient on apixaban 2.5 mg twice daily with ESRD on hemodialysis, with no active bleeding and normal liver function—the INR normalized after discontinuing apixaban without any reversal agents. 1

Immediate Assessment

• Assess for active bleeding: Check for gross hemorrhage, occult bleeding (hemoccult testing, hematuria), intracranial hemorrhage symptoms (headache, altered mental status, focal neurological deficits), or bleeding at any anatomical site. 3

• Evaluate bleeding risk factors: Advanced age, renal failure (particularly ESRD on dialysis), alcohol use, concomitant antiplatelet agents or NSAIDs, history of stroke, and treated hypertension all increase bleeding risk independent of INR. 3, 1

• Review medication list and recent changes: Cefazolin and other antibiotics can cause true INR elevation through vitamin K depletion, which could coexist with apixaban's laboratory effect. 4

• Check renal function: Apixaban undergoes 27% renal clearance, and impaired renal function (especially ESRD) can lead to drug accumulation and genuinely increased anticoagulant effect despite the INR being an unreliable marker. 1

Management Algorithm

If NO Active Bleeding:

• Hold the next dose(s) of apixaban temporarily while assessing the clinical situation and determining if drug accumulation is present. 1

• Do NOT administer vitamin K—it is ineffective for direct Factor Xa inhibitors and only reverses vitamin K antagonists like warfarin. 5, 3

• Recheck INR 24-48 hours after holding apixaban to confirm the INR decreases as drug levels decline, which confirms the elevation was due to apixaban interference. 1

• Consider measuring apixaban drug levels (anti-Factor Xa activity calibrated for apixaban) if available, as this provides actual assessment of anticoagulant effect rather than relying on INR. 1, 2

• Investigate potential causes of drug accumulation: Acute kidney injury, drug interactions (particularly with strong CYP3A4 or P-glycoprotein inhibitors), or dosing errors. 1

If Active Bleeding is Present:

• For minor bleeding: Hold apixaban and provide supportive care with local hemostatic measures; the drug's half-life is 12 hours, so anticoagulant effect will diminish within 24-48 hours. 1

• For major or life-threatening bleeding: Administer andexanet alfa, the specific reversal agent for Factor Xa inhibitors including apixaban. 5

  • Low-dose andexanet alfa: 400 mg IV bolus followed by 4 mg/min infusion for up to 120 minutes (480 mg total) if the last apixaban dose was ≤5 mg taken <8 hours prior or any dose taken ≥8 hours prior. 5
  • High-dose andexanet alfa: 800 mg IV bolus followed by 8 mg/min infusion for up to 120 minutes (960 mg total) if the last apixaban dose was >5 mg taken <8 hours prior. 5

• If andexanet alfa is unavailable: Administer four-factor prothrombin complex concentrate (4F-PCC) or activated PCC (aPCC) as second-line hemostatic agents, though these are less effective for Factor Xa inhibitors than for warfarin. 5

• Consider activated charcoal if apixaban ingestion occurred within 2-4 hours and there is no contraindication (e.g., altered mental status, aspiration risk). 5

Common Pitfalls to Avoid

• Do not treat the INR number itself—the INR >8.0 does not indicate the same bleeding risk as it would in a patient on warfarin, and vitamin K administration is completely ineffective and inappropriate. 1, 2

• Do not assume the patient has vitamin K deficiency or liver disease based solely on elevated INR while on apixaban; baseline INR prior to starting apixaban and liver function tests help differentiate. 1

• Do not use INR for ongoing monitoring of apixaban therapy—it is not validated for this purpose and will lead to inappropriate clinical decisions. 1, 2

• Do not overlook genuine drug accumulation in renal failure—while the INR is unreliable, patients with ESRD or acute kidney injury may have truly elevated apixaban levels requiring dose adjustment or discontinuation. 1

Restarting Anticoagulation

• Once bleeding is controlled or the clinical situation is clarified, consider restarting apixaban at an appropriate dose based on renal function, bleeding risk, and thrombotic risk. 5

• In patients with ESRD on hemodialysis, apixaban 2.5 mg twice daily results in drug exposure similar to 5 mg twice daily in patients with normal renal function, but there are no FDA-approved indications for apixaban in dialysis patients. 1

• If the elevated INR was due to a concomitant issue (e.g., cefazolin-induced vitamin K deficiency), address the underlying cause before resuming full anticoagulation. 4